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C. M. Bojanowski, J. Tuo, R. J. Ross, D. Shen, E. Y. Chew, C.-C. Chan; Variants Within HTRA1 and LOC387715 Independent of CFH Are Associated With an Increased Risk of Age-Related Macular Degeneration in a Caucasian Population. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3653.
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Substantial evidence exists supporting the role of genetic variation in the development and pathogenesis of both advanced geographic (dry) and neovascular (wet) forms of age-related macular degeneration (AMD). An allelic variant within complement factor H (CFH) located on chromosome 1q32 has been identified as a major AMD risk factor. Since the identification of this key susceptibility gene, other variants located on chromosome region 10q26, notably LOC387715 and HTRA1, have been reported as additional AMD susceptibility genes. The goal of this study is to further investigate the association of CFH, LOC387715, and HTRA1 and AMD and the possible gene interactions between them.
Genomic DNA was subjected to PCR amplification following extraction from peripheral blood collected from a Caucasian population of 132 age-matched controls without clinical signs of AMD and 102 advanced AMD patients. LOC387715 (rs10490924), CFH intron (rs380390), and HTRA1 (rs11200638) SNPs were genotyped using taqman and PCR-RFLP techniques. HTRA1 data was further analyzed by AMD sub-type. Chi-square testing was performed for case-control analysis. Logistic regression was applied to study potential gene interaction.
HTRA1 variant allele distribution differed significantly (OR = 1.613 (95% CI: 1.110, 2.401), P= 0.0128) between AMD patients and controls with allele frequencies of 37.7% (82/204) in AMD cases and 29.2% (77/264) in the controls. We have reported a LOC387715 variant to be significantly increased in the AMD cases (OR = 7.23, P = 0.010-0.0008). An additive model was observed indicating a strong synergic effect of LOC387715 and CFH intron SNPs with a combined OR of 24.11(Ross et al. IOVS 2007). In this small sample population, a higher OR (OR=3.119) was achieved for HTRA1 in wet AMD cases as compared to dry AMD cases (OR=1.685). No evidence of epistasis between CFH and HTRA1 was observed (P=0.4360).
In the present study, we have replicated the associations between CFH and LOC387715 and AMD. Additionally, these results support an association between an HTRA1 variant and increased AMD risk in the Caucasian population. This risk is marginally higher in wet AMD cases. Interestingly, gene interaction was not observed between HTRA1 and CFH in this population. Larger sample sizes are needed to clarify the association between HTRA1 and the AMD disease sub-types.
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